The long-term goal of the proposed research is to elucidate the connections between immunity and aging. There is mounting evidence that the response and resistance of higher organisms to microbial challenges comes at a cost. While bolstered immunity offers protection against invaders, it may have adverse effects on other organismal functions. Immunity effectors may elicit damage to host cells and tissues, which ultimately could lead to functional deficits. They can also place substantial energy demands on the cellular machinery, which may result in trade-offs that negatively impact the maintenance of cellular homeostasis. The detrimental effects of the immune response on functioning and cellular homeostasis are further exacerbated in older individuals, where adaptive immunity declines and innate immunity exhibits a shift toward an excessive response and inflammation. Functional analyses have established that the immune response is impaired in older animals, resulting in inadequate response and compromised signaling, which in turn can result in cancer and other age-related diseases. If mechanisms of the proper control over immune signaling are elucidated, appropriate interventions can be designed and applied. During the proposed research we will define the mechanisms that govern the inter-relationship between innate immunity and aging. Coincident with the over-active immune response in older organisms is the change to a more pro- oxidizing redox state. We suggest that changes in redox during aging is a major factor in deregulation of the immune system, and that a family of thiol-dependent peroxidases, peroxiredoxins, known as key regulators of redox signaling, are likely to serve critical roles in modulation of the immune response during aging. To test the hypothesis that peroxiredoxins are responsible for chronic over-activation of the immune stress response in older individuals, we will adapt the Drosophila model system, which has a rich genetic heritage with well developed tools for modulating gene expression. Drosophila possesses a full complement of peroxidoxins, all having mammalian orthologues, and furthermore, the immune signaling and stress-response pathways of Drosophila are remarkably similar to those found in mammals. We determined that one of the peroxiredoxins, peroxiredoxin 5 (dPrx5) regulates immune and stress responses and promotes longevity. During the proposed research we will i) determine specific pathways by which dPrx5 modulates the immune response and position it within these pathways, ii) delineate molecular mechanisms, by which dPrx5 modulates immune signaling and iii) determine age-related differences in the regulation of the immune signaling by dPrx5. Together, these studies should permit a mechanistic understanding of peroxiredoxin-mediated immune response during aging and to establish the key links between longevity and immune signaling in the fly, which will help guide similar analyses in higher organisms. PUBLIC HEALTH RELEVANCE: Aging is characterized by malfunctioning of immunity. Deregulation of the immune response during aging can result in cancer and other age-related diseases. The proposed study is aimed at elucidating the mechanisms that underlie such deregulation in order to develop proper interventions.